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bp(GO:macroautophagy)

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Entity

Name
macroautophagy
Namespace
go
Namespace Version
20180921
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/go-names.belns

Appears in Networks 10

Perilous journey: a tour of the ubiquitin–proteasome system v1.0.0

The Biology of Proteostasis in Aging and Disease v1.0.0

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing v1.0.0

Interplay of pathogenic forms of human tau with different autophagic pathways v1.0.1

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies v1.0.0

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

Alzheimer’s disease and the autophagic-lysosomal system v1.0.0

The Ubiquitin–Proteasome System and the Autophagic–Lysosomal System in Alzheimer Disease v1.0.0

Molecular Chaperone Functions in Protein Folding and Proteostasis v1.0.0

Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection v1.0.0

In-Edges 63

a(MESH:Ubiquitin) regulates bp(GO:macroautophagy) View Subject | View Object

For instance, ubiquitin can recruit other factors to mediate various cellular responses such as signaling, gene regulation, endocytosis, macro-autophagy, and DNA repair PubMed:24457024

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Consistent with a role of autophagy in disease, AD patient tissues exhibit impaired initiation of macroautophagy and an excess of autophagic vacuoles in dystrophic neurites, possibly due to impaired targeting of the vacuolar ATPase to the lysosome (86, 87). PubMed:25784053

Appears in Networks:

a(CHEBI:"5-chloro-7-iodoquinolin-8-ol") increases bp(GO:macroautophagy) View Subject | View Object

Indeed, clioquinol countered disruption of autophagy by chloroquine in retinal cells, reduced Aβ42 accumulation in CHO cells expressing APP and mutant presenilin 1 and diminished amyloid misfolding and aggregation in Tg2576 AD mice 196,197 . PubMed:30116051

Appears in Networks:

a(CHEBI:ambroxol) increases bp(GO:macroautophagy) View Subject | View Object

It increased expression of βGCase, normalized autophagy and accelerated degradation of α-synuclein in a stem cell model of dopaminergic neurons derived from patients with PD bearing mutations in βGCase 200 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Parkinson Disease

a(CHEBI:chlorohydroquinone) decreases bp(GO:macroautophagy) View Subject | View Object

Indeed, clioquinol countered disruption of autophagy by chloroquine in retinal cells, reduced Aβ42 accumulation in CHO cells expressing APP and mutant presenilin 1 and diminished amyloid misfolding and aggregation in Tg2576 AD mice 196,197 . PubMed:30116051

Appears in Networks:

a(CHEBI:cilostazol) increases bp(GO:macroautophagy) View Subject | View Object

Cilostazol (a phosphodiesterase 3 inhibitor) clears Aβ42 from neuronal cell lines by promoting autophagy, upregulating beclin 1, ATG5 and LC3, downregulating mTORC1 and inducing lysosomal cathepsin B; these actions of cilostazol involve activation of SIRT1 as well as upstream Tyr172 phosphorylation of AMPK 108,162,163 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:curcumin) increases bp(GO:macroautophagy) View Subject | View Object

The natural product curcumin induced macro- autophagy and protected rotenone-treated dopaminer- gic neurons 141 in addition to accelerating the elimination of mutant α-synuclein-A53T by repressing mTORC1 in a cellular model of early-onset PD, although it also exerts other actions such as inhibition of p300-mediated pro- tein acetylation and of aggregation 142,143 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:fisetin) increases bp(GO:macroautophagy) View Subject | View Object

Moreover, the flavonol fisetin stimulated auto- phagic degradation of phosphorylated tau in cortical neu- rons via mTORC1-dependent activation of TFEB and the cytoprotective transcription factor nuclear factor eryth- roid 2-related factor 2 (NFE2L2) 149 . Fisetin also reduced Aβ accumulation in an APP/PS1 mouse model of AD 150 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(CHEBI:nilotinib) increases bp(GO:macroautophagy) View Subject | View Object

Inactivation of ABL1 with brain-penetrant nilotinib conferred neuroprotective autophagy in mouse models of PD 153 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

a(PUBCHEM:16240819) increases bp(GO:macroautophagy) View Subject | View Object

An unusual approach to augmenting autophagosome formation is represented by the brain- penetrant autophagy enhancer 99 (AUTEN-99), which blocks myotubularin-related protein 14 (MTMR14, also known as Jumpy), a phosphatase that inhibits the phos- phoinositide 3-kinase (PI3K)-mediated generation of the autophagosome membrane (FIG. 3) . AUTEN-99 aug- mented autophagic flux in isolated neurons, increased markers of autophagy in mouse brain and slowed neuro- degeneration in D. melanogaster models of PD and HD 181 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

complex(p(HGNC:BCL2), p(HGNC:BECN1)) decreases bp(GO:macroautophagy) View Subject | View Object

Disruption of this Bcl-2–beclin 1 complex is an alternative approach for promoting autophagy, as achieved in mouse fibroblasts by the BH3 mimetic ABT-737 (REF.177) . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Machado-Joseph Disease

p(FPLX:AMPK) increases bp(GO:macroautophagy) View Subject | View Object

The heterotrimeric serine/threonine kinase 5ʹ‑AMP‑ activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) trigger autophagy and repress mitophagy 3,10,20–23 (BOX 2; FIG. 3) . PubMed:30116051

Appears in Networks:

p(FPLX:mTORC1) increases bp(GO:macroautophagy) View Subject | View Object

The heterotrimeric serine/threonine kinase 5ʹ‑AMP‑ activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) trigger autophagy and repress mitophagy 3,10,20–23 (BOX 2; FIG. 3) . PubMed:30116051

Appears in Networks:

p(FPLX:mTORC1) decreases bp(GO:macroautophagy) View Subject | View Object

One major strategy for promoting autophagy is the relief of its repression by mTORC1. PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons

p(HGNC:ABL1) decreases bp(GO:macroautophagy) View Subject | View Object

Tyrosine-protein kinase ABL1 is a proto- oncogene that negatively regulates autophagy, partly acting upstream of the RAC serine/threonine-protein kinase (AKT)–mTORC1 axis. PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

p(HGNC:FOXO1) increases bp(GO:macroautophagy) View Subject | View Object

Other transcription factors that posi- tively regulate autophagy include forkhead box protein O1 (FOXO1) and FOXO3 (REF.22) . PubMed:30116051

Appears in Networks:

p(HGNC:FOXO3) increases bp(GO:macroautophagy) View Subject | View Object

Other transcription factors that posi- tively regulate autophagy include forkhead box protein O1 (FOXO1) and FOXO3 (REF.22) . PubMed:30116051

Appears in Networks:

p(HGNC:SESN2) increases bp(GO:macroautophagy) View Subject | View Object

Supporting the relevance of sestrin 2, it has been shown to protect dopaminergic neurons from the neurotoxin rotenone via AMPK-transduced autophagy 247 . PubMed:30116051

Appears in Networks:

p(HGNC:SESN2) increases bp(GO:macroautophagy) View Subject | View Object

Sestrin 2 over expression also prompted mTORC1-dependent autophagy in cortical neurons in a presenilin-knockout model of AD. PubMed:30116051

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:SIRT1) increases bp(GO:macroautophagy) View Subject | View Object

Because the class III deacetylase NAD- dependent protein deacetylase sirtuin 1 (SIRT1) requires nicotinamide adenine dinucleotide (NAD) to sustain its activity, this positive regulator of autophagy may also be considered a sensor 24 . PubMed:30116051

Appears in Networks:

p(HGNC:STAT3) decreases bp(GO:macroautophagy) View Subject | View Object

Conversely, repression is effected by signal transducer and activator of transcrip- tion 3 (STAT3) and possibly zinc-finger protein with KRAB and SCAN domains 3 (ZKSCAN3), although its role has been disputed 22,32 . PubMed:30116051

Appears in Networks:

p(HGNC:TFEB) increases bp(GO:macroautophagy) View Subject | View Object

Unc-51-like kinase 1 (ULK1) is primarily an autophagy-initiating protein 3,10,19 , as is the mTORC1- suppressed transcrip- tion factor EB (TFEB), which orchestrates the synthesis of lysosomal and other proteins critical for maintaining ALN flux 20–23 . PubMed:30116051

Appears in Networks:

tloc(p(HGNC:TFEB), fromLoc(MESH:Cytoplasm), toLoc(MESH:"Cell Nucleus")) increases bp(GO:macroautophagy) View Subject | View Object

mTORC1 also restrains autophagy by preventing nuclear translo- cation of TFEB 20 . PubMed:30116051

Appears in Networks:

p(HGNC:ULK1) increases bp(GO:macroautophagy) View Subject | View Object

Unc-51-like kinase 1 (ULK1) is primarily an autophagy-initiating protein 3,10,19 , as is the mTORC1- suppressed transcrip- tion factor EB (TFEB), which orchestrates the synthesis of lysosomal and other proteins critical for maintaining ALN flux 20–23 . PubMed:30116051

Appears in Networks:

p(HGNC:ZKSCAN3) decreases bp(GO:macroautophagy) View Subject | View Object

Conversely, repression is effected by signal transducer and activator of transcrip- tion 3 (STAT3) and possibly zinc-finger protein with KRAB and SCAN domains 3 (ZKSCAN3), although its role has been disputed 22,32 . PubMed:30116051

Appears in Networks:

p(MGI:Mapt, var("p.Ala152Thr")) increases bp(GO:macroautophagy) View Subject | View Object

We found that abundance of autophagic vacuoles (autophagosomes + autolysosomes) significantly increased in cells expressing either of the two tau mutants (Fig. 4d,e). This increase was mainly due to higher content of autolysosomes (red puncta) (Fig. 4d,e), in support of increased macroautophagic flux PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Ala152Thr")) increases bp(GO:macroautophagy) View Subject | View Object

In fact, increased macroautophagy may be responsible for the increase in the degradation of long-lived proteins that we observed for both mutant forms of tau under these conditions (Fig. 3b) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases bp(GO:macroautophagy) View Subject | View Object

We found that abundance of autophagic vacuoles (autophagosomes + autolysosomes) significantly increased in cells expressing either of the two tau mutants (Fig. 4d,e). This increase was mainly due to higher content of autolysosomes (red puncta) (Fig. 4d,e), in support of increased macroautophagic flux PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
High
MeSH
Brain

p(MGI:Mapt, var("p.Pro301Leu")) increases bp(GO:macroautophagy) View Subject | View Object

In fact, increased macroautophagy may be responsible for the increase in the degradation of long-lived proteins that we observed for both mutant forms of tau under these conditions (Fig. 3b) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
High
MeSH
Brain

a(CHEBI:sirolimus) increases bp(GO:macroautophagy) View Subject | View Object

A quite different strategy is to target tau clearance—e.g., by rapamycin that induces macroautophagy [175], inhibitors of Hsp90 chaperone protein that binds to misfolded proteins or by immunotherapeutic approaches [176]. PubMed:26751493

Appears in Networks:

a(CHEBI:"alpha,alpha-trehalose") increases bp(GO:macroautophagy) View Subject | View Object

Protein clearance in animal models has been successfully demonstrated using several small molecules and drugs that enhance induction of macroautophagy reduces AD-relevant pathology, including rapamycin in 3xTGAD mice [32] and temsirolimus in P301S transgenic mice [156] and trehalose in APP/PS1 and P301S MAPT transgenic mice [157,158]. PubMed:29758300

Appears in Networks:

a(CHEBI:"amyloid-beta") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

For instance, while accumulation of Aβ activates the mTOR signaling pathway and subsequently blocks macroautophagy, rapamycin reduces the Aβ load by enhancing macroautophagy [32] PubMed:29758300

Appears in Networks:

a(CHEBI:"methylene blue") increases bp(GO:macroautophagy) View Subject | View Object

Methylene blue, a contrast agent that can reduce tau misfolding, has also been shown to induce macroautophagy, as indicated by elevated Beclin 1 and LC3-II levels and reduced tau and p62 levels in organotypic neuronal cultures and a mouse model of FTD [159] PubMed:29758300

Appears in Networks:

a(CHEBI:Temsirolimus) increases bp(GO:macroautophagy) View Subject | View Object

Protein clearance in animal models has been successfully demonstrated using several small molecules and drugs that enhance induction of macroautophagy reduces AD-relevant pathology, including rapamycin in 3xTGAD mice [32] and temsirolimus in P301S transgenic mice [156] and trehalose in APP/PS1 and P301S MAPT transgenic mice [157,158]. PubMed:29758300

Appears in Networks:

a(CHEBI:lipid) regulates bp(GO:macroautophagy) View Subject | View Object

Decreased triglyceride breakdown upon macroautophagy inhibition and impairment in macroautophagy by lipid supplementation demonstrates reciprocally interrelated regulation of autophagy and lipids [72] PubMed:29758300

Appears in Networks:

a(CHEBI:sirolimus) increases bp(GO:macroautophagy) View Subject | View Object

For instance, while accumulation of Aβ activates the mTOR signaling pathway and subsequently blocks macroautophagy, rapamycin reduces the Aβ load by enhancing macroautophagy [32] PubMed:29758300

Appears in Networks:

a(CHEBI:sirolimus) increases bp(GO:macroautophagy) View Subject | View Object

Protein clearance in animal models has been successfully demonstrated using several small molecules and drugs that enhance induction of macroautophagy reduces AD-relevant pathology, including rapamycin in 3xTGAD mice [32] and temsirolimus in P301S transgenic mice [156] and trehalose in APP/PS1 and P301S MAPT transgenic mice [157,158]. PubMed:29758300

Appears in Networks:

complex(p(HGNC:TFEB), p(INTERPRO:"cAMP response element binding (CREB) protein")) increases bp(GO:macroautophagy) View Subject | View Object

Under starvation or stress, TFEB translocates to the nucleus and binds the CRE element to promote expression of macroautophagy and lysosomal genes [88]. PubMed:29758300

Appears in Networks:

p(HGNC:MAPT, var("p.Ala152Thr")) increases bp(GO:macroautophagy) View Subject | View Object

For example, in tau A152T iPSC-derived cortical neurons, total and phosphorylated Tau levels are elevated, particularly the insoluble forms [133], which is associated with decreases in UPS function as measured by total polyubiquitinated proteins and an upregulation of macroautophagy markers. PubMed:29758300

Appears in Networks:

composite(p(HGNC:PTEN), p(HGNC:TFEB)) increases bp(GO:macroautophagy) View Subject | View Object

Activation of PTEN, another inducer of macroautophagy, by TFEB is indispensable for this TFEB-mediated increase in macroautophagy [89] PubMed:29758300

Appears in Networks:

p(HGNC:PTEN) increases bp(GO:macroautophagy) View Subject | View Object

Activation of PTEN, another inducer of macroautophagy, by TFEB is indispensable for this TFEB-mediated increase in macroautophagy [89] PubMed:29758300

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p(HGNC:ATG7) increases bp(GO:macroautophagy) View Subject | View Object

Compromised macroautophagy, via the genetic suppression of Atg7, leads to the blockade of Aβ secretion and contributes to the subsequent diminution in extracellular Aβ plaque load PubMed:29758300

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p(HGNC:BECN1) association bp(GO:macroautophagy) View Subject | View Object

These results may be attributed to coincidental evidence of the involvement of Beclin 1 in VPS34-mediated trafficking pathways including macroautophagy and endocytosis [37], both of which are pronouncedly affected in AD pathology [38] PubMed:29758300

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p(HGNC:PICALM) regulates bp(GO:macroautophagy) View Subject | View Object

However, recent work provides direct evidence that PICALM can also modulate macroautophagy, via its role in SNARE endocytosis to clear tau aggregates [102]. PubMed:29758300

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p(HGNC:TREM2) increases bp(GO:macroautophagy) View Subject | View Object

Recent work by Ulland et al. has also discovered an additional function of TREM2 in the maintenance of microglial macroautophagy and metabolism PubMed:29758300

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

p(HGNC:VPS35, var("?")) decreases bp(GO:macroautophagy) View Subject | View Object

VPS35 mutations have been shown to disrupt macroautophagy [113] and mitochondrial function [114] and are associated with AD and PD [102,115]. PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Since Nixon and colleagues first reported the pathological evidence of defective macroautophagy in EM images in the AD brain, similar observations have been made in cellular and animal models of AD [2,3,7,14] PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Defects in macroautophagy in AD are supported by additional lines of evidence PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Maintenance of neuronal macroautophagy can counteract AD pathology [22,23]. PubMed:29758300

Appears in Networks:
Annotations
MeSH
Neurons

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

These results may be attributed to coincidental evidence of the involvement of Beclin 1 in VPS34-mediated trafficking pathways including macroautophagy and endocytosis [37], both of which are pronouncedly affected in AD pathology [38] PubMed:29758300

Appears in Networks:

path(MESH:"Amyotrophic Lateral Sclerosis") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154] PubMed:29758300

Appears in Networks:

path(MESH:"Bulbo-Spinal Atrophy, X-Linked") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154] PubMed:29758300

Appears in Networks:

path(MESH:"Niemann-Pick Disease, Type C") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154] PubMed:29758300

Appears in Networks:

path(MESH:"Parkinson Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154] PubMed:29758300

Appears in Networks:

path(MESH:"Spastic Paraplegia, Hereditary") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154] PubMed:29758300

Appears in Networks:

p(HGNC:BAG3) increases bp(GO:macroautophagy) View Subject | View Object

BAG1 targets proteins for degradation by the UPS, whereas BAG3 mediates degradation by macroautophagy. PubMed:23746257

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bp(GO:"autophagy of nucleus") isA bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

bp(GO:aggrephagy) isA bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

bp(GO:mitophagy) isA bp(GO:macroautophagy) View Subject | View Object

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bp(GO:pexophagy) isA bp(GO:macroautophagy) View Subject | View Object

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bp(GO:reticulophagy) isA bp(GO:macroautophagy) View Subject | View Object

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bp(GO:ribophagy) isA bp(GO:macroautophagy) View Subject | View Object

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bp(GO:xenophagy) isA bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Out-Edges 34

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Consistent with a role of autophagy in disease, AD patient tissues exhibit impaired initiation of macroautophagy and an excess of autophagic vacuoles in dystrophic neurites, possibly due to impaired targeting of the vacuolar ATPase to the lysosome (86, 87). PubMed:25784053

Appears in Networks:

bp(GO:macroautophagy) increases deg(p(HGNC:MAPT, pmod(HBP:HBP00007))) View Subject | View Object

Moreover, the flavonol fisetin stimulated auto- phagic degradation of phosphorylated tau in cortical neu- rons via mTORC1-dependent activation of TFEB and the cytoprotective transcription factor nuclear factor eryth- roid 2-related factor 2 (NFE2L2) 149 . Fisetin also reduced Aβ accumulation in an APP/PS1 mouse model of AD 150 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

bp(GO:macroautophagy) increases deg(p(MGI:Mapt)) View Subject | View Object

In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this agerelated disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk-associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Neurons

bp(GO:macroautophagy) decreases deg(p(MGI:Mapt)) View Subject | View Object

Macroautophagy blockage resulted in preferential accumulation of A152T, but not WT and P301L tau (Fig. 2e,f) PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

bp(GO:macroautophagy) increases deg(p(MGI:Mapt, var("p.Ala152Thr"))) View Subject | View Object

Macroautophagy blockage resulted in preferential accumulation of A152T, but not WT and P301L tau (Fig. 2e,f) PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

bp(GO:macroautophagy) decreases deg(p(MGI:Mapt, var("p.Pro301Leu"))) View Subject | View Object

Macroautophagy blockage resulted in preferential accumulation of A152T, but not WT and P301L tau (Fig. 2e,f) PubMed:29024336

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

bp(GO:macroautophagy) causesNoChange deg(p(MGI:Mapt, var("p.Pro301Leu"))) View Subject | View Object

The most notable difference between the two tau mutants was the inability of P301L to undergo degradation by CMA or by macroautophagy PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
Medium
MeSH
Brain

bp(GO:macroautophagy) increases deg(a(MESH:Proteins)) View Subject | View Object

In fact, increased macroautophagy may be responsible for the increase in the degradation of long-lived proteins that we observed for both mutant forms of tau under these conditions (Fig. 3b) PubMed:29024336

Appears in Networks:
Annotations
MeSH
Multivesicular Bodies
Confidence
High
MeSH
Brain

bp(GO:macroautophagy) decreases p(HGNC:MAPT) View Subject | View Object

A quite different strategy is to target tau clearance—e.g., by rapamycin that induces macroautophagy [175], inhibitors of Hsp90 chaperone protein that binds to misfolded proteins or by immunotherapeutic approaches [176]. PubMed:26751493

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Since Nixon and colleagues first reported the pathological evidence of defective macroautophagy in EM images in the AD brain, similar observations have been made in cellular and animal models of AD [2,3,7,14] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Defects in macroautophagy in AD are supported by additional lines of evidence PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Maintenance of neuronal macroautophagy can counteract AD pathology [22,23]. PubMed:29758300

Appears in Networks:
Annotations
MeSH
Neurons

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

These results may be attributed to coincidental evidence of the involvement of Beclin 1 in VPS34-mediated trafficking pathways including macroautophagy and endocytosis [37], both of which are pronouncedly affected in AD pathology [38] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) increases deg(a(HBP:"protein aggregates")) View Subject | View Object

With neurons profoundly relying on macroautophagy for clearance of toxic protein aggregates, impairment in the proteolytic systems ultimately results in progressive neuronal death, a common feature in several neurodegenerative diseases [27]. PubMed:29758300

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bp(GO:macroautophagy) increases deg(a(HBP:"protein aggregates")) View Subject | View Object

Lastly, macroautophagy, but not UPS or CMA can clear protein aggregates. PubMed:29758300

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bp(GO:macroautophagy) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

Increased Aβ generation and accumulation in lysosomes suggest that Aβ metabolism, at least partially, is regulated by macroautophagy [3,14,32–34]. PubMed:29758300

Appears in Networks:
Annotations
MeSH
Lysosomes

bp(GO:macroautophagy) negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

For instance, while accumulation of Aβ activates the mTOR signaling pathway and subsequently blocks macroautophagy, rapamycin reduces the Aβ load by enhancing macroautophagy [32] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

In line with this, reduced Beclin 1 levels, as seen in AD models [16], increase the levels of intracellular and extracellular Aβ peptides, supporting the role of macroautophagy in the generation and degradation of Aβ [33,35]. PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

In line with this, reduced Beclin 1 levels, as seen in AD models [16], increase the levels of intracellular and extracellular Aβ peptides, supporting the role of macroautophagy in the generation and degradation of Aβ [33,35]. PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) increases sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

Compromised macroautophagy, via the genetic suppression of Atg7, leads to the blockade of Aβ secretion and contributes to the subsequent diminution in extracellular Aβ plaque load PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) increases sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

This inhibition of Aβ secretion during macroautophagy deficiency results in aberrant cytosolic accumulation of Aβ, which ultimately evokes neurodegeneration accompanied with memory loss. PubMed:29758300

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bp(GO:macroautophagy) association p(HGNC:BECN1) View Subject | View Object

These results may be attributed to coincidental evidence of the involvement of Beclin 1 in VPS34-mediated trafficking pathways including macroautophagy and endocytosis [37], both of which are pronouncedly affected in AD pathology [38] PubMed:29758300

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bp(GO:macroautophagy) increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Compromised macroautophagy, via the genetic suppression of Atg7, leads to the blockade of Aβ secretion and contributes to the subsequent diminution in extracellular Aβ plaque load PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

Wang et al., using an N2a neuroblastoma cell line that expresses the repeat domain of tau with an FTD-17 mutation (TauRDΔK280), has demonstrated that tau aggregates can be degraded by macroautophagy [48] PubMed:29758300

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bp(GO:macroautophagy) increases deg(a(CHEBI:triglyceride)) View Subject | View Object

Decreased triglyceride breakdown upon macroautophagy inhibition and impairment in macroautophagy by lipid supplementation demonstrates reciprocally interrelated regulation of autophagy and lipids [72] PubMed:29758300

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bp(GO:macroautophagy) negativeCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Niemann-Pick Disease, Type C") View Subject | View Object

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Bulbo-Spinal Atrophy, X-Linked") View Subject | View Object

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Spastic Paraplegia, Hereditary") View Subject | View Object

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) increases a(GO:autophagosome) View Subject | View Object

During macroautophagy, an elongated “isolation” membrane created from a preautophagosomal structure sequesters a region of cytoplasm to form a double- membrane-limited autophagosome (Fig. 5). PubMed:22908190

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bp(GO:macroautophagy) increases deg(p(HGNC:MAPT, frag("?"))) View Subject | View Object

Incomplete charperone-mediated autophagy of tau generates fragments that aggregate and are cleared by macroautophagy (Wang et al. 2009). PubMed:22908190

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bp(GO:macroautophagy) increases bp(GO:"autophagosome-lysosome fusion") View Subject | View Object

These processes are distinguished from macroautophagy, in which an isolation membrane expands to engulf a portion of the cell, eventually fusing to form a new autophagic vacuole that subsequently fuses with a lysosome [12]. PubMed:18930136

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bp(GO:macroautophagy) increases deg(p(HGNC:SNCA)) View Subject | View Object

The neuronal protein α-synuclein, for example, can be degraded by the UPS, macroautophagy and chaperone-mediated autophagy [26,29]. PubMed:18930136

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About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.